The long term goal of this project is to understand how oligodendrocytes, which are glial cells of the central nervous system, ensheath specific axons with specialized, proteolipid-rich myelin membrane. To myelinate axons, oligodendrocytes extend numerous membrane processes than spirally wrap axons. However, not all axons are myelinated. Based on observations that brain activity can modify myelin, we hypothesize that activity-dependent signals from axons influence which axons are selected for myelination. Using zebrafish as a model system, this project combines in vivo live cell imaging with genetic and pharmacological manipulations to investigate mechanisms that guide formation of myelin on specific axons in response to neuronal activity. Specific Aim 1 will test the hypothesis that neuronal activity provides axons with a competitive advantage for myelination through direct observation of ensheathment and myelination of identifiable axons that have different electrical activities in vivo. Specific Aim 2 will use genetic and pharmacological approaches and live imaging to test the hypothesis that neuronal activity promotes myelin sheath growth on select axons by activating the PI3K-Akt-mTor signaling pathway. Specific Aim 3 will test a hypothesis that activity-mediated signaling promotes the stability and translation of mRNAs that encode myelin proteins and identify new activity- regulated transcripts. Completion of these aims will substantially extend our understanding of the cellular mechanisms by which oligodendrocytes choose axons for myelination and key molecules that promote activity- regulated myelin membrane growth. The results of this project have the potential for important new insights to learning, memory and psychiatric disease and to provide a foundation for designing therapeutic strategies to promote myelination of brains damaged by disease or injury.